Development and Characterisation of KRASmulti Inhibitors for the Treatment of KRAS Mutant Pancreatic Ductal Adenocarcinoma

Pancreatic ductal adenocarcinoma (PDAC) is predicted to become the second most common cause of cancer related death within the next decade. Late detection and limited therapeutic options drive the dismal prognosis for PDAC patients. Activating mutations within the KRAS gene occur within the vast majority (>85%) of PDAC tumors. KRAS mutations occur at an early stage within PDAC development but remain necessary for continued tumor growth. Clinical responses observed in patients with KRASG12C mutant PDAC treated with selective KRASG12C inhibitors have driven drug development programmes that can address other, more frequently occurring KRAS alleles. Here we report the characterization of a KRASmulti inhibitor, BI-2493, that potently inhibits the proliferation of mutant KRAS PDAC cancer cell lines in vitro. The DMPK properties of the compound have been optimized so that oral administration resulted in regression of KRAS mutant PDAC xenograft models. These data support the continued development of compounds capable of addressing the most prevalent KRAS mutant alleles in PDAC with the potential to provide a therapeutic option to patients in an indication with a high unmet medical need. Citation Format: Antonio Tedeschi, Otmar Schaaf, Michael Gmachl, Lorenz Herdeis, Francesca Rocchetti, Johannes Popow, Fiorella Schischlik, Daniel Gerlach, Jesse Lipp, Joachim Bröker, Andreas Mantoulidis, Chris Smethurst, Dirk Kessler, Jark Boettcher, Tobias Wunberg, Valeria Santoro, Alex Waterson, Jason Phan, Andrew Little, Jason Abbott, Qi Sun, Stephen Fesik, Darryl Mcconnell, Mark A. Pearson, Norbert Kraut, Dorothea Rudolph. Development and characterisation of KRASmulti inhibitors for the treatment of KRAS mutant pancreatic ductal adenocarcinoma [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Pancreatic Cancer; 2023 Sep 27-30; Boston, Massachusetts. Philadelphia (PA): AACR; Cancer Res 2024;84(2 Suppl):Abstract nr B103.